Understanding the Role of Toll-Like Receptors 9 in Breast Cancer

Breast cancer is a significant global issue, ranking as the second most common cancer among women worldwide and a leading cause of cancer-related deaths. Although the exact causes of this increase remain unclear, factors such as genetics, epigenetics, obesity, sedentary lifestyle, tobacco use, and vitamin D deficiency have been implicated. The Toll-like receptor 9 (TLR9) is recognized for its role in inflammation and innate immunity; however, its specific involvement in breast cancer pathogenesis requires further investigation. This study aims to systematically review the existing literature on TLR9 expression in normal and cancerous breast tissue, providing current knowledge and identifying gaps. Relevant articles in English were from PubMed, Scopus, and Google Scholar, with the inclusion criteria focusing on studies evaluating TLR9 mRNA and protein expression. The review found that TLR9 mRNA and protein exhibit variable expressions in both normal and cancerous breast tissue, highlighting the need for further research to clarify TLR9’s role in breast cancer.This research received no external funding

Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort.

Background: The relationships between cockroach and mouse allergen exposure, anti-cockroach and anti-mouse IgE, and wheeze, rhinitis, and atopic dermatitis in children as young as age 3 years are of public health importance but have not been thoroughly evaluated. Objective: We hypothesized that inner-city children might have anti-cockroach and anti-mouse IgE by age 3 years, and their presence would be associated with respiratory and atopic symptoms. Methods: Children were followed prospectively from birth through age 3 years (n = 404). Residential levels of cockroach and mouse allergens, sera levels of anti-cockroach and anti-mouse IgE, and parental report of wheeze, rhinitis, and atopic dermatitis were measured. Results: The odds of early wheeze were significantly higher among children who had IgE to cockroach (odds ratio [OR], 3.3; 95% CI, 1.8-6.2), mouse (OR, 4.6; 95% CI, 2.3-9.0), or both (OR, 9.7; 95% CI, 3.4-27.3). The odds of rhinitis or atopic dermatitis were also higher among children with IgE to cockroach, mouse, or both. Higher IgE class to cockroach and mouse was associated with wheeze and atopic dermatitis (tests for trend, P < .002). Conclusions: Children age 2 to 3 years who have anti-cockroach and anti-mouse IgE are at increased risk of wheeze and atopy. Moreover, a dose-response relationship was found between higher IgE class and increased prevalence of wheeze, rhinitis, or atopic dermatitis. These findings indicate the importance of reducing exposure to cockroach and mouse allergens for susceptible children.VoRSUNY DownstateEnvironmental and Occupational Health SciencesN/

DNA methylation and hormone receptor status in breast cancer

BACKGROUND: We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA). RESULTS: DNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity. CONCLUSIONS: Higher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0184-7) contains supplementary material, which is available to authorized users

The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis

A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro–B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro–B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPα and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process

The Role of Glucocorticoid Receptor in the Racial/Ethnic Disparity of Aggressive Breast Cancer

Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women worldwide. There is a well-documented variation in breast cancer incidence and mortality across nations and among racial/ethnic groups within these nations. In the United States, the incidence of breast cancer is lower among African American and Hispanic women when compared with white women, yet, as a group African American and Hispanic women have a more aggressive disease at diagnosis and worse survival outcomes. The reasons for racial disparity in breast cancer mortality are largely unknown but likely multifactorial involving environmental and biological factors. A number of epidemiological studies have shown that the cellular alterations resulting from chronic psychosocial stress may increase breast cancer development and progression. One of the primary mediators of stress is glucocorticoid. Glucocorticoid is a steroid hormone with a physiological and pathological role in the body; it acts via its cytoplasmic receptor, the glucocorticoid receptor (GCR). Upon binding to glucocorticoid, GCR is activated and released from a chaperone complex. Activated GCR travels to the nucleus to regulate a myriad of physiological processes such as mammary development and differentiation, inflammation, apoptosis as well as glucose and fatty acid metabolism-processes which have been associated with breast cancer development and progression. The main hypothesis is that alterations in the level or localization of GCR might interfere with the glucocorticoid response, resulting in aberrant downstream cellular responses such as decreased apoptosis and chronic inflammation that might contribute to aggressive breast cancer. And if these characteristics vary by race/ethnicity then this may play a role in the pathogenesis of the racial/ethnic disparity of breast cancer. The overarching theme of this research is to understand the role of GCR in breast cancer and its potential involvement in racial/ethnic disparities. To answer our research question, we used data from the Breast Cancer Care in Chicago (BCCC), a large, multiethnic population of incident breast cancer cases between the ages of 30 and 79 with stored biological samples and linked clinical, genetic ancestry and sociodemographic data

Abstract A91: Does psychosocial stress play a role in the etiology of aggressive breast cancer? A cross-sectional study

Abstract Background: Greater levels of fear, anxiety or isolation (psychosocial stress) have been hypothesized to negatively alter the sympathetic-parasympathetic autonomic nervous system and suppress immune function, physiologic effects that in turn might impact breast tumor aggressiveness. There is a paucity of cohort data relating psychosocial stress to breast tumor aggressiveness. We examined associations between patient-reported psychosocial stress with aggressive breast cancer in a cross-sectional study of 989 recently diagnosed breast cancer patients (397 non-Hispanic white, 411 non-Hispanic black, 181 Hispanic). We examined associations of psychosocial stress with breast cancer aggressiveness and whether racial/ethnic differences in psychosocial stress might account for disparities in breast cancer aggressiveness. A major assumption of these analyses was that patients reporting greater psychosocial stress at interview (2–3 months after diagnosis) would have also reported relatively greater psychosocial stress had they been interviewed prior to diagnosis. Methods: Psychosocial stress was assessed using the Cohen perceived stress 4 item subscale, the UCLA felt loneliness scale (3 items), and the Cockburn psychological consequences scale (12 items). These three scales loaded onto a single factor in factor analysis, and were used to create a single, standardized psychosocial stress score (Cronbach's alpha=0.56). Breast cancer aggressiveness was defined as Hormone (estrogen and progesterone) receptor negative tumors and tumors high in histologic grade. Differences in psychosocial stress scores were evaluated via t-tests, and logistic regression was used to estimate odds ratios for breast cancer aggressiveness corresponding to a one standard deviation increase in psychosocial stress score. All reported p-values are two-sided. Because aggressive breast cancer tends to lead to a later stage at diagnosis and an earlier age at diagnosis, adjustment for these variables may inappropriately attenuate the association of interest between psychosocial stress and tumor aggressiveness. Nonetheless, because psychosocial stress was measured after diagnosis, we adjusted for age and stage in some models. Results: Patient reported psychosocial stress was one-third of a standard deviation higher for patients with receptor negative vs. positive disease (mean score difference = 0.32, p=0.0003), and higher for patients with high vs. low or intermediate grade disease (difference = 0.17, p=0.03). Compared to nH-Whites, psychosocial stress scores were higher for nh-Black patients (difference = 0.22, p=0.006), and higher for Hispanic patients (difference = 0.44, p&amp;lt;0.001). In logistic regression, the unadjusted association of greater psychosocial stress with receptor negative disease (OR=1.38, p&amp;lt;0.0005), was somewhat attenuated after adjusting for sociodemographics (OR=1.27, p=0.01), and further attenuated with additional adjustment for age and stage at diagnosis (OR=1.22, p=0.06). The association between psychosocial stress and high grade disease that was evident in unadjusted (OR=1.18, p=0.03) and partially adjusted analyses (OR=1.17, p=0.05) disappeared with additional adjustment for age and stage at diagnosis (OR=1.10, p=0.30). In path models, there were significant indirect paths from minority ethnicity to both receptor negative and high grade disease via psychosocial stress (p=0.02 and 0.02, respectively), accounting for roughly 10% of ethnic differences in tumor aggressiveness. Conclusions: In this cross-sectional study, greater levels of fear, anxiety or isolation were associated with more aggressive breast cancer, consistent with a potential role for psychosocial stress in the etiology of breast cancer aggressiveness. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A91.</jats:p

Prognostic Value of SGK1 and Bcl-2 in Invasive Breast Cancer

It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression

Abstract 583: Physiological concentrations of genistein reduced ER-α promoter methylation and increased ER-α expression in prostate cancer cells

Abstract Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. The lower incidence and mortality rates of prostate cancer in Asian population were correlated to the high dietary consumption of isoflavone-rich soy. One of the most abundant and potent isoflavones in soy is genistein which has an estradiol like structure and high affinity to estrogen receptor-α (ER-α). It has been suggested that genistein exerts its anti-cancer effects through binding to ER-α, the later has anti-proliferative and pro-apoptotic effects in prostate cancer. ER-α is mainly expressed in prostate epithelial cells and is downregulated in localized prostate cancer with increasing grade from Prostatic Intraepithelial Neoplasia (PIN) through low to high Gleason grade. This expression pattern supports the notion of a tumor suppressor role of ER-α. Therefore, ER-α agonists may be potential chemopreventive and therapeutic agents for prostate cancer. One of the mechanisms by which ER-α is suppressed in prostate cancer is promoter methylation, the extent of which correlates with the ER-α expression level which in turn may be linked to the degree of aggressiveness of prostate cancer. We examined the effects of physiological range of genistein concentrations (0.5, 1, and 10µM) on ER-α promoter methylation and ER-α expression in LNCaP, LAPC-4, and PC-3 prostate cancer cells that exhibit various basal levels of ER-α expression. We demonstrated for the first time that genistein caused a significant dose-dependent reduction in ER-α promoter methylation in LNCaP and LAPC-4 cells, using methylation specific PCR. There was a corresponding dose-related increase in ER-α mRNA and protein levels in these two cell lines assayed by quantitative RT-PCR and immunoblotting, respectively. However, ER-α expression levels and ER-α promoter methylation were not changed in PC-3 cells, which could be attributed to the low basal level of ER-α promoter methylation and the high basal level of ER-α expression in this cell line. These findings suggest that physiological concentrations of genistein is capable of reactivating tumor suppressor pathways by reversing ER-α promoter methylation with a subsequent restoration of the level of ER-α expression in prostate cancer cells that have higher basal levels of methylation. (Supported in part by Grant No. CA116195) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 583. doi:1538-7445.AM2012-583</jats:p